The Journal of antimicrobial chemotherapy · 2026
Juvenile toxicity and developmental safety of Zintrodiazine, a novel antimalarial candidate, in Wistar rats.
СтатьяНазвание и аннотация: Перевод в очереди
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Kadu Hitesh A, Rajwadi Viral I, Shah Jigar V, Chauhan Vipul B, Panchal Pratik P, Bhatt Laxit K, Patel Jitendra H, Ranvir Ramchandra K, Patel Harilal, Trivedi Ravi R, Kusmider Beata, Tornesi Belen, Nyska Abraham, Sundar Rajesh, Jain Mukul R
Аннотация
OBJECTIVES: Zintrodiazine (ZY-19489) is a novel triaminopyrimidine-class antimalarial with potent activity against Plasmodium falciparum, including resistant strains. To support paediatric development and meet regulatory requirements, we conducted a comprehensive juvenile toxicity study of Zintrodiazine in rats, focusing on growth, neurodevelopment and toxicokinetics.
METHODS: Wistar rats were administered vehicle and 30, 45 or 60 mg/kg/day Zintrodiazine orally from postnatal day (PND) 10-45, followed by a 4-week recovery (PND 46-73). Endpoints included clinical observations, neurobehavioural assays (open field, acoustic startle/pre-pulse inhibition and Morris water maze), sexual maturation, bone growth, clinical pathology, organ weights and histopathology. Toxicokinetic profiling at PND 21 and 45 assessed age- and sex-related exposure differences.
RESULTS: No treatment-related mortality, clinical signs or developmental impairment were observed. Body weight, food intake, sexual maturation and femur length were unaffected. Neurobehavioural performance remained normal across all assays. Transient, non-dose-dependent changes in liver and renal biomarkers observed at terminal phase resolved at the end of recovery. Minimal, reversible vacuolation consistent with phospholipidosis was observed in the liver, lymphoid, pulmonary and adrenal tissues at ≥30 mg/kg/day, without inflammation or necrosis. Systemic exposure was dose-proportional; females exhibited higher parent compound and metabolite (ZY-20486) levels, while metabolite exposure declined with age, consistent with maturational biotransformation. The no-observed-adverse-effect level was 60 mg/kg/day (Cmax ≤1572 ng/mL; AUClast ≤35 592 h·ng/mL).
CONCLUSIONS: Zintrodiazine demonstrated a favourable juvenile safety profile, with no adverse effects on growth, neurodevelopment or sexual maturation at clinically relevant exposures. These findings provide critical regulatory data supporting progression into paediatric clinical trials and highlight Zintrodiazine's potential as a safe and effective antimalarial for children.
METHODS: Wistar rats were administered vehicle and 30, 45 or 60 mg/kg/day Zintrodiazine orally from postnatal day (PND) 10-45, followed by a 4-week recovery (PND 46-73). Endpoints included clinical observations, neurobehavioural assays (open field, acoustic startle/pre-pulse inhibition and Morris water maze), sexual maturation, bone growth, clinical pathology, organ weights and histopathology. Toxicokinetic profiling at PND 21 and 45 assessed age- and sex-related exposure differences.
RESULTS: No treatment-related mortality, clinical signs or developmental impairment were observed. Body weight, food intake, sexual maturation and femur length were unaffected. Neurobehavioural performance remained normal across all assays. Transient, non-dose-dependent changes in liver and renal biomarkers observed at terminal phase resolved at the end of recovery. Minimal, reversible vacuolation consistent with phospholipidosis was observed in the liver, lymphoid, pulmonary and adrenal tissues at ≥30 mg/kg/day, without inflammation or necrosis. Systemic exposure was dose-proportional; females exhibited higher parent compound and metabolite (ZY-20486) levels, while metabolite exposure declined with age, consistent with maturational biotransformation. The no-observed-adverse-effect level was 60 mg/kg/day (Cmax ≤1572 ng/mL; AUClast ≤35 592 h·ng/mL).
CONCLUSIONS: Zintrodiazine demonstrated a favourable juvenile safety profile, with no adverse effects on growth, neurodevelopment or sexual maturation at clinically relevant exposures. These findings provide critical regulatory data supporting progression into paediatric clinical trials and highlight Zintrodiazine's potential as a safe and effective antimalarial for children.